4,5,5a,6-tetrahydro-3H-isoxazolo(5,4,3-kl)acridines, pharmaceutical compositions and use

ABSTRACT

There are disclosed compounds having the formula &lt;CHEM&gt;  where X is hydrogen, loweralkyl, loweralkoxy, halogen or trifluoromethyl, and R when present is hydrogen, loweralkyl, allyl, arylloweralkyl,   - @ - Cl or   - @ - NH - R, wherein R1 is loweralkyl, &lt;CHEM&gt; n being 2, 3 or 4 and R2 and R3 being independently loweralkyl, or the group &lt;CHEM&gt;  taken as a whole constituting &lt;CHEM&gt; which compounds are useful as analgesic agents and also for the treatment of various memory dysfunctions characterized by a decreased cholinergic function such as Alzheimer&#39;s disease.

This invention relates to compounds having the formula ##STR6## where Xis hydrogen, loweralkyl, loweralkoxy, halogen or trifluoromethyl, and

R when present is hydrogen, loweralkyl, allyl, arylloweralkyl, ##STR7##wherein R₁ is loweralkyl, --CH₂ C.tbd.CH, ##STR8## n being 2, 3 or 4 andR₂ and R₃ being independently loweralkyl, or the group ##STR9## taken asa whole constituting ##STR10## which compounds are useful as analgesicagents and also for the treatment of various memory dysfunctionscharacterized by a decreased cholinergic function such as Alzheimer'sdisease.

The dotted lines appearing in Formula I and other formulas used in thisspecification and appended claims signify the fact that when the group Ris present, the chemical bond between the 5a-carbon and 6-nitrogen is asingle bond and that when R is absent, the bond between the 5a-carbonand 6-nitrogen is a double bond.

Throughout the specification and the appended claims, a given chemicalformula or name shell encompass all stereo, geometrical and opticalisomers thereof where such isomers exist, as well as pharmaceuticallyacceptable acid addition salts thereof and solvates thereof such as forinstance hydrates.

The following definitions shall apply throught the specification and theappended claims.

Unless otherwise stated or indicated, the term loweralkyl denotes astraight or branched alkyl group having from 1 to 6 carbon atoms.Examples of said loweralkyl include methyl, ethyl, n-propyl, iso-butyl,pentyl and hexyl.

Unless otherwise stated or indicated, the term halogen shall meanfluorine, chlorine, bromine or iodine.

Unless otherwise stated or indicated, the term aryl shall mean a phenylgroup optionally mono-substituted with a loweralkyl, loweralkoxy,halogen or trifluoromethyl group.

The compounds of this invention can be prepared by utilizing one or moreof the synthetic steps described below.

Throughout the description of the synthetic steps, the definitions of X,R, R₁, R₂, R₃ and n are as given above unless otherwise stated orindicated, and other nomenclatures shall have their respective meaningsgiven in their first appearances.

STEP A:

A compound of Formula II is allowed to react with hydrazoic acid (NH₃)in the presence of a protic acid or Lewis acid to afford a compound ofFormula III. This reaction is typically conducted by using NaN₃ andconcentrated H₂ SO₄ as well as a suitable medium such as dichloromethaneat a temperature of about 0° to 40° C. ##STR11##

The starting compound of Formula II where X is hydrogen is disclosed inAkhrem et al., Synthesis, page 43 (1978).

STEP B

Compound III is allowed to react with NaCNBH₄ in a routine manner knownto the art to afford a compound of Formula IV. ##STR12##

STEP C

Compound IV is allowed to react with a halide compound of the formula R₄-Hal, where R₄ is loweralkyl, allyl or arylloweralkyl and Hal ischlorine or bromine, to afford a compound of Formula V. ##STR13##

The above reaction is typically conducted in the presence of aninorganic base such as K₂ CO₃ and a suitable medium such asdimethylformamide at a temperature of about 25° to 100° C.

STEP D

Compound IV is allowed to react with phosgene to afford a compound ofFormula VI. ##STR14##

The above reaction is typically conducted in the presence of a suitableacid scavenger such as triethylamine and a suitable solvent such asdichloromethane at a temperature of about 0° to 40° C.

STEP E

Compound VI is allowed to react with an amine of the formula ##STR15##where R₅ is loweralkyl, --CH₂ C.tbd.CH or ##STR16## to afford a compoundof Formula VII. ##STR17##

The above reaction is typically conducted in a suitable solvent such ascarbon tetrachloride at a temperature of about 0° to 45° C.

STEP F

As an alternative to STEPS D and E, compound IV is allowed to react withan isocyanate of the formula R₅ --NCO to afford compound VII.

    (IV)+R.sub.5 --NCO→                                 (VII)

The above reaction is typically conducted in a suitable solvent such ascarbon tetrachloride at a temperature of about 0° to 45° C.

STEP G

A compound of Formula VIIa obtained in STEP E or F is allowed to reactwith formaldehyde and a secondary amine of the formula ##STR18## toafford a compound of Formula VIII (Mannich reaction). ##STR19##

The above reaction is typically conducted in the presence of a catalyticamount of cuprous chloride (CuCl) and a suitable solvent such astetrahydrofuran at a temperature of about 50° to 150° C.

STEP H

Compound VIII is converted to a cis or trans double bond compound ofFormula IX. ##STR20##

For preparing the trans isomer, typically this reaction is conductedwith the aid of lithium aluminum hydride and a suitable medium such asTHF at a temperature of about 0° to 80° C. For preparing the cis isomer,typically this reaction is conducted with the aid of a suitable catalystsuch as 5% Pd/BaSO₄ and a suitable medium such as methanol at atemperature of about 25°-50° C.

STEP I

Compound VIII is catalytically hydrogenated in a routine manner known tothe art to afford a compound of Formula X. ##STR21##

Typically this reaction is conducted with the aid of a suitable catalystsuch as 5% Pd/C and a suitable medium such as ethanol at a temperatureof about 25° to 50° C.

The compounds of Formula I of the present invention are useful asanalgesic agents due to their ability to alleviate pain in mammals. Theactivity of the compound is demonstrated in the2-phenyl-1,4-benzoquinone-induced writhing test in mice, a standardassay for analgesia [Proc. Soc. Exptl. Biol. Med., 95, 729 (1957)].Table 1 shows results of the test for of some of the compounds of thisinvention.

                  TABLE 1                                                         ______________________________________                                        ANALGESIC ACTIVITY                                                            (Phenylquinone Writhing)                                                                           Analgesic PQW                                                                 % Inhibition of                                                               Writhing at                                              Compound             20 mg/kg., S.C.                                          ______________________________________                                        6-Ethylaminocarbonyl-4,5,5a,6-                                                                     44%                                                      tetrahydro-3H-isoxazolo-                                                      [5,4,3-kl]acridine                                                            N-[2-(4-Morpholinyl)ethyl]-                                                                        52%                                                      4,5,5a,6-tetrahydro-3H-                                                       isoxazolo[5,4,3-kl]acridine                                                   6-carboxamide                                                                 N-(2-Propynyl)-4,5,5a,6-                                                                           29%                                                      tetrahydro-3H-isoxazolo-                                                      [5,4,3-kl]acridine-6-carboxamide                                              N-[4-(1-Pyrrolidinyl)-2-                                                                           33%                                                      butyn-1-yl]-4,5,5a,6-                                                         tetrahydro-3H-isoxazolo[5,4,3-kl]-                                            acridine-6-carboxamide                                                        (Reference Compound)                                                          Propoxyphene         50% at 3.9 mg/kg, s.c.                                   ______________________________________                                    

The compounds of Formula (I) of the present invention can also be usedfor the treatment of various memory dysfunctions characterized by adecreased cholinergic function such as Alzheimer's disease.

This utility can be ascertained by determining the ability of thesecompounds to inhibit the activity of the enzyme acetylcholinesterase andthereby increase the acetylcholine levels in the brain.

CHOLINESTERASE INHIBITION ASSAY

The ability to inhibit acetylchlinesterase was determined by thephotometric method of Ellman et al., Biochem. Pharmacol. 7, 88 (1961).Results of some of the compounds of this invention are presented inTable 2 along with those of some reference compounds.

                  TABLE 2                                                         ______________________________________                                        Cholinesterase Inhibition                                                     Compound             IC.sub.50 (molar conc.)                                  ______________________________________                                        4,5-Dihydro-3H-isoxazolo-                                                                          3.9 × 10.sup.-6                                    [5,4,3-kl]acridine                                                            4,5,5a,6-Tetrahydro-3H-                                                                            1.3 × 10.sup.-5                                    isoxazolo[5,4,3-kl]acridine                                                   (Reference Compounds)                                                         9-Amino-1,2,3,4-tetrahydroacridine                                                                 3.1 × 10.sup.-7                                    Physostigmine        6.0 × 10.sup.-9                                    ______________________________________                                    

This utility can also be ascertained by determining the ability of thesecompounds to restore cholinergically deficient memory in the DarkAvoidance Assay. In this assay mice are tested for their ability toremember an unpleasant stimulus for a period of 24 hours. A mouse isplaced in a chamber that contains a dark compartment; a strongincadescent light drives it to the dark compartment, where an electricshock is administered through metal plates on the floor. The animal isremoved from the testing apparatus and tested again, 24 hours later, forthe ability to remember the electric shock.

If scopolamine, an anticholinergic that is known to cause memoryimpairment, is administered before an animal's initial exposure to thetest chamber, the animal re-enters the dark compartment shortly afterbeing placed in the test chamber 24 hours later. This effect ofscopolamine is blocked by an active test compound, resulting in agreater interval before re-entry into the dark compartment.

The results for an active compound are expressed as the percent of agroup of animals in which the effect of scopolamine is blocked, asmanifested by an increased interval between being placed in the testchamber and re-entering the dark compartment. Results of Dark AvoidanceAssay for representative compounds of this invention and a referencecompound are presented in Table 3.

                  TABLE 3                                                         ______________________________________                                        Dark Avoidance Assay                                                                                     % of animals with                                                  Dose       scopolamine induced                                                mg/kg      memory deficit                                     Compound        body weight                                                                              reversal                                           ______________________________________                                        4,5-Dihydro-3H-isoxazolo-                                                                     0.63       20%                                                [5,4,3-kl]acridine                                                            6-(2-Propenyl)-4,5,5a,6-                                                                      1.25       27%                                                tetrahydro-3H-isoxazolo-                                                      [5,4,3-kl]acridine                                                            Physostigmine (Reference)                                                                     0.31       20%                                                ______________________________________                                    

Effective quantities of the compounds of the invention may beadministered to a patient by any of the various methods, for example,orally as in capsule or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions. The free base final products, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable acid addition salts for purposes ofstability, convenience of crystallization, increased solubility and thelike.

Acids useful for preparing the pharmaceutically acceptable acid additionsalts of the invention include inorganic acids such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as wellas organic acids such as tartaric, citric, acetic, succinic, maleic,fumaric and oxalic acids.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an ediblecarrier, or they may be enclosed in gelatin capsules, or they may becompressed into tablets. For the purpose of oral therapeuticadministration, the active compounds of the invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gum and thelike. These preparations should contain at least 0.5% of activecompounds, but may be varied depending upon the particular form and mayconveniently be between 4% to about 70% of the weight of the unit. Theamount of active compound in such compositions is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 milligrams of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as micro-crystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, cornstarch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweeting agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes, coloring and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but may be varied between 0.5 and about 30% of the weightthereof. The amount of active compound in such compositions is such thata suitable dosage will be obtained. Preferred compositions andpreparations according to the present inventions are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of activecompound.

Examples of the compounds of this invention include

4,5-dihydro-3H-isoxazolo[5,4,3-kl]acridine;

4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine;

6-(2-propenyl)-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine;

6-benzyl-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine;

6-(4-fluorobenzyl)-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine;

6-ethylaminocarbonyl-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine;

4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine-6-carbonyl chloride;

N-[2-(4-morpholinyl)ethyl]-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-k]-acridine-6-carboxamide;

N-(2-propynyl)-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine;

N-[4-(1-pyrrolidinyl)-2-butyn-1-yl]-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine-6-carboxamide;

N-[4-(4-morpholinyl)-2-butyn-1-yl]-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine-6-carboxamide;

The following examples are presented in order to illustrate thisinvention.

EXAMPLE 1 4,5-Dihydro-3H-isoxazolo[5,4,3-kl]acridine

3-Phenyl-4-oxo-4,5,6,7-tetrahydrobenz[1,2-d]isoxazole (6.0 g) wasdissolved in 40 ml conc. H₂ SO₄ and then dichloromethane (60 ml) wasadded. NaN₃ (2.0 g) was added portionwise at such a rate that foamingcould be controlled. After 90 minutes, the reaction mixture was pouredinto ice/water and conc. HCl was added until the precipitated aminesulfate dissolved. The dichloromethane layer was separated and theaqueous phase was washed with additional dichloromethane. The aqueousphase was made basic with 50% NaOH and ice (up to pH 1-4) and then withNaHCO₃ (up to pH 8). The product was extracted into dichloromethane andthen flushed over a short alumina column before concentration underreduced pressure. Recrystallization from EtOAc/hexane gave 1.85 g ofproduct, m.p. 149°-150° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.13 H.sub.10 N.sub.2 O:                                                   74.27% C 4.79% H   13.33% N                                   Found:          74.50% C 4.87% H   13.39% N                                   ______________________________________                                    

EXAMPLE 2 4,5,5a,6-Tetrahydro-3H-isoxazolo[5,4,3-kl]acridine

In 100 ml glacial acetic acid was dissolved 4.75 g4,5-dihydro-3H-isoxazolo[5,4,3-kl]acridine. To the mechanically stirredsolution under nitrogen was added 2.84 g of sodium cyanoborohydride. Thereaction was complete after 0.5 hour at room temperature. The reactionmixture was neutralized with excess aqueous sodium carbonate andextracted with dichloromethane (DCM). The DCM was dried over MgSO₄,filtered and concentrated to a solid. The solid was purified by flashchromatography and recrystallized from 1:1 DCM/hexanes to yield 2.78 gof powder, m.p. 152°-154° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.13 H.sub.12 N.sub.2 O:                                                   73.57% C 5.70% H   13.20% N                                   Found:          73.84% C 5.81% H   13.22% N                                   ______________________________________                                    

EXAMPLE 36-(2-Propenyl)-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine

In 20 ml dry dimethylformaldehyde (DMF) were combined 4.00 g4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine, 3.26 ml allylbromide and 8 g milled K₂ CO₃. The mixture was heated at 90° C. andmechanically stirred. Every hour 2 ml more allyl bromide was added.After 3 hours, the reaction was complete as observed by TLC. The mixturewas partitioned between water and EtOAc. The EtOAc layer wasconcentrated to a solid which was purified by passing over a silicacolumn (flash chromatography). The product obtained in this manner wasrecrystallized twice from 20% EtOAc/hexanes to yield 2.99 g solid whichwas dried in vacuo, m.p. 114°-117° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.16 H.sub.16 N.sub.2 O:                                                   76.16% C 6.39% H   11.10% N                                   Found:          75.90% C 6.39% H   11.15% N                                   ______________________________________                                    

EXAMPLE 4 6-Benzyl-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine

In 50 ml dry DMF were combined 2.10 g4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine, 2.0 g milledanhydrous K₂ CO₃ and 1.3 ml benzylbromide. The mechanically stirredmixture was heated under nitrogen at 90° C. for 18 hours. During thefirst 4 hours, 1 ml benzyl bromide was added every hour as TLC analysisindicated it was being consumed. For the work-up, the mixture was pouredin excess water and extracted with DCM. The DCM layer was concentratedto an oil and the oil was purified on a silica column (flashchromatography) using DCM as an eluent. The product-containing fractionswere combined and concentrated to a solid. The solid was recrystallizedfrom EtOAc/hexanes and dried in a vacuum desiccator to yield 2.10 g ofproduct, m.p. 162°-163.5° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.20 H.sub.28 N.sub.2 O:                                                   79.44% C  6.00% H   9.26% N                                   Found:          79.60% C  6.23% H   9.17% N                                   ______________________________________                                    

EXAMPLE 56-(4-Fluorobenzyl)-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine

In 40 ml dry DMF were combined 3.00 g4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine, 8.8 ml4-fluorobenzylbromide and 3 g milled K₂ CO₃. The mixture was stirredmechanically under nitrogen at ambient temperature for 2 days duringwhich the reaction was complete. The reaction mixture was poured intoexcess water and extracted with DCM. The DCM layer was concentrated to aresidue and the residue was triturated with 1:1 methanol/water andrecrystallized from 1:1 DCM/hexanes to yield after drying 2.21 gneedles, m.p. 214° C. (dec.).

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.20 H.sub.27 FN.sub.2 O:                                                  74.98% C  5.35% H   8.74% N                                   Found:          75.06% C  5.52% H   8.78% N                                   ______________________________________                                    

EXAMPLE 66-Ethylaminocarbonyl-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine

In 20 ml CCl₄ were combined 5.00 g4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine and 9 ml ethylisocyanate. The mixture was refluxed for two days. After the first day,9 ml more ethyl isocyanate was added. The reaction mixture was thencooled in ice and the precipitate filtered. The precipitate wasrecrystallized from 1:1 DCM/hexanes and dried in vacuo at 80° C. toyield 3.91 g crystals, m.p. 189° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.10 H.sub.17 N.sub.3 O.sub.2 :                                            67.83% C 6.05% H   14.83% N                                   Found:          67.82% C 6.05% H   14.84% N                                   ______________________________________                                    

EXAMPLE 7 4,5,5a,6-Tetrahydro-3H-isoxazolo[5,4,3-kl]acridine-6-cabonylchloride

In 50 ml of dichloromethane was dissolved 4.08 g of4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine. Phosgene in benzene(26 ml of 12.5% phogene in benzene) was then added all in one portion.This solution was then chilled with an ice/water bath as a solution oftriethylamine (2.92 g) in 20 ml of dichloromethane was added dropwise.After the addition was complete (30 minutes), the reaction mixture waswashed with dilute hydrochloric acid and then dried and concentrated.The residue obtained in this manner was recrystallized fromdichloromethane/hexane to give 3.66 g of product, m.p. 189° C. (d).

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.14 H.sub.11 ClN.sub.2 O.sub.2 :                                          61.20% C 4.03% H   10.20% N                                   Found:          60.83% C 4.13% H   9.98% N                                    ______________________________________                                    

EXAMPLE 8N-[2-(4-Morpholinyl)ethyl]-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine-6-carboxamide

In 100 ml CCl₄ were combined 2.50 g4,5,5a,6-tetrahydro-3H-isoxazolo-5,4,3-kl]acridine-6-carbamoyl chlorideand 1.43 ml 4-(2-aminoethyl)morpholine. The reaction mixture wasrefluxed 1/2 hour and 1.43 ml more of morpholine was added and refluxresumed for 1/2 hour more. The reaction mixture was diluted with DCM andwashed with saturated NaHCO₃ solution. The organics were dried overMgSO₄, filtered and concentrated to a solid which was recrystallizedonce from 1:1 DCM/hexanes and once from 1:1 Et₂ O/hexanes to yield afterdrying in vacuo at 80° C. 2.25 g solid, m.p. 176°-178° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.20 H.sub.24 N.sub.4 O.sub.3 :                                            65.20% C 6.57% H   15.21% N                                   Found:          65.13% C 6.59% H   15.29% N                                   ______________________________________                                    

EXAMPLE 9N-(2-Propynyl)-4,5,5a,6-tetrahydro-3H-isoxazolo-[5,4,3-kl]acridine-6-carboxamide

In 100 ml CCl₄ were combined 3.34 g4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridin-6-carbamyl chlorideand 1.84 ml propargylamine. The solution was refluxed 2 hours, duringwhich a white precipitate formed. The reaction mixture was poured intoice/3N HCl and the biphasic mixture was filtered. The precipitate wasrecrystallized twice from MeOH/water to yield 2.00 g of product, m.p.220 C. (decomposes).

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.17 H.sub.15 N.sub.3 O.sub.2 :                                            69.61% C 5.15% H   14.33% N                                   Found:          69.56% C 5.29% H   14.49% N                                   ______________________________________                                    

EXAMPLE 10N-[4-(1-Pyrrolidinyl)-2-butyn-1-yl]-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine-6-carboxamide

In 200 ml THF were combined 2.40 gN-(2-propynyl)-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridin-6-carboxamide,0.98 g paraformaldehyde, 0.75 ml pyrrolidene and a few mg of CuClcatalyst. The reaction mixture was refluxed for 1 hour, but no furtherreaction occurred, so again 0.98 g paraformaldehyde, 0.75 ml amine andCuCl catalyst were added. After 4 hours, the reaction was complete. Themixture was concentrated to a residue and partitioned between EtOAc and10% NaCO₃. The EtOAc phase was dried over MgSO₄, filtered, concentratedto 100 ml and flushed through an alumina column with EtOAc. The productwas concentrated to a solid, which was recrystallized twice from 1:1DCM/hexanes and dried overnight at 80° C. to yield 2.18 g crystals, m.p.132° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.22 H.sub.24 N.sub.4 O.sub.2 :                                            70.19% C 6.43% H   14.88% N                                   Found:          69.85% C 6.48% H   14.86% N                                   ______________________________________                                    

EXAMPLE 11N-[4-(4-Morpholinyl)-2-butyn-1-yl]-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine-6-carboxamide

In 200 ml THF were combined 2.35 gN-(2-propynyl)-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridin-6-carboxamide,0.96 g paraformamide, 0.77 ml morpholine and 50 mg CuCl catalyst. Thereaction mixture was refluxed four hours and then paraformamide (0.96g), morpholine (0.77 ml) and CuCl were again added. After 10 hours ofreflux, the reaction mixture was concentrated and the residuepartitioned between EtOAc and 10% Na₂ CO₃. The EtOAc phase was driedover MgSO₄ and passed through an alumina column (about 200 g) with EtOAceluent. As some starting material eluted with the product, the productwas extracted into 3N HCl from EtOAc. The 3N HCl solution was separated,made basic and extracted into DCM. The DCM evaporated and hexanes wereadded to effect crystallization to yield 1.15 g powder, m.p. 186° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.22 H.sub.24 N.sub.4 O.sub.3 :                                            67.33% C 6.16% H   14.28% N                                   Found:          66.99% C 6.11% H   14.23% N                                   ______________________________________                                    

We claim:
 1. A compound of the formula ##STR22## where X is hydrogen,loweralkyl, loweralkoxy, halogen or trifluoromethyl, andR when presentis hydrogen, loweralkyl, allyl, arylloweralkyl, ##STR23## wherein R₁ isloweralkyl, --CH₂ C.tbd.CH, ##STR24## n being 2, 3 or 4 and R₂ and R₃being independently loweralkyl, or the group ##STR25## taken as a wholeconstituting ##STR26## or a pharmaceutically acceptable acid additionsalt thereof.
 2. The compound as defined in claim 1, where X ishydrogen.
 3. The compound as defined in claim 1, which is4,5-dihydro-3H-isoxazolo[5,4,3-kl]acridine.
 4. The compound as definedin claim 1, which is 4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine.5. The compound as defined in claim 1, which is6-(2-propenyl)-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine. 6.The compound as defined in claim 1, which is6-benzyl-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine.
 7. Thecompound as defined in claim 1, which is6-(4-fluorobenzyl)-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine.8. The compound as defined in claim 1, which is6-ethylaminocarbonyl-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine.9. The compound as defined in claim 1, which is4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine-6-carbonyl chloride.10. The compound as defined in claim 1, which isN-[2-(4-morpholinyl)ethyl]-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine-6-carboxamide.11. The compound as defined in claim 1, which isN-(2-propynyl)-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine. 12.The compound as defined in claim 1, which isN-[4-(1-pyrrolidinyl)-2-butyn-1-yl]-4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine-6-carboxamide.13. The compound as defined in claim 1, which isN-[4-(4-morpholinyl)-2-butyn-1-yl]-4,5,5a,6-tetrahydro-3H-isoxazolo-[5,4,3-kl]acridine-6-carboxamide.14. A pharmaceutical composition comprising a compound as defined inclaim 1 in an amount effective for alleviating pain or a memorydysfunction characterized by a decreased cholinergic function and asuitable carrier therefor.
 15. A method of treating a patient in need ofrelief from pain which comprises administering to such a patient aneffective pain alleviating amount of a compound as defined in claim 1.16. A method of treating a patient in need of relief from a memorydysfunction characterized by a decreased cholinergic function whichcomprises administering to such patient an effective amount of acompound as defined in claim 1.